Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A brain-specific multifunctional calmodulin-dependent protein kinase, calmodulin-dependent protein kinase IV, which exhibited characteristic properties quite different from those of calmodulin-dependent protein kinase II, was purified approximately 230-fold from rat cerebellum. The purified preparation gave two protein bands with molecular weights of 63,000 (alpha) and 66,000 (beta) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, both of which showed protein kinase activity as examined by the activity gel method. The molecular weight of the enzyme was estimated as about 67,000 from sedimentation coefficient (3.2 S) and Stokes radius (50 A), indicating a monomeric structure of the enzyme. The enzyme phosphorylated smooth muscle myosin light chain, synapsin I, microtubule-associated protein 2, tau protein, myelin basic protein, histone H1, and tyrosine hydroxylase in a Ca2+/calmodulin dependent manner, suggesting that the enzyme is a multifunctional calmodulin-dependent protein kinase capable of phosphorylating a large number of substrates. A synthetic peptide, Lys-Ser-Asp-Gly-Gly-Val-Lys-Lys-Arg-Lys-Ser-Ser-Ser-Ser, was found to be a specific substrate for this kinase and, using this peptide as substrate, the distribution of the enzyme activity in various rat tissues was examined. The activity was found in cerebral cortex, brain stem, and cerebellum, most abundantly in cerebellum, but other tissues tested, including liver, spleen, kidney, lung, heart, skeletal muscle, and adrenal gland showed very little activity.
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PMID:Purification and characterization of a brain-specific multifunctional calmodulin-dependent protein kinase from rat cerebellum. 130 65

Lewy bodies are cytoskeletal inclusions associated with neuronal injury and death in idiopathic Parkinson's disease and other neurodegenerative disorders. The chemical composition of the 8-10-nm fibrils of the Lewy body is unknown, although they are related to both normal cytoskeletal elements and paired helical filaments of Alzheimer neurofibrillary tangles. From the Lewy body-rich cerebral cortex of patients with diffuse Lewy body disease we have isolated intact Lewy bodies using a high salt buffer/nonionic detergent gradient centrifugation procedure and extracted the constitutive fibrils with urea and sodium dodecyl sulfate. Urea/detergent-resistant Lewy body fibrils were solubilized with formic acid and found to contain a single protein band of 68 kDa, which was not found in identically prepared normal brain homogenates. The Lewy body derived-polypeptide was recognized on immunoblots by a polyclonal antibody that reacted with both the 68-kDa neurofilament subunit and the microtubule-associated protein tau. The 68-kDa Lewy body protein was not labeled by the monoclonal antibody tau-1 despite prior in vitro enzymatic dephosphorylation. We conclude that the detergent-insoluble component of the cortical Lewy body fibril shares epitopes with neurofilament and tau and may be a posttranslationally modified derivative of either neurofilament or tau with substantially altered biochemical and immunologic properties.
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PMID:Detergent-insoluble cortical Lewy body fibrils share epitopes with neurofilament and tau. 137 81

From bovine brain microtubules we purified tau protein kinase I (TPKI, Mr 45,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and tau protein kinase II (TPKII) whose activity was attributed to a 30-kDa protein on SDS-PAGE by affinity-labeling using an ATP analog. Both kinases were activated by tubulin. TPKII, but not TPKI, phosphorylated tau fragment peptides previously used for detection of a Ser/ThrPro kinase activity. Therefore, TPKII was considered to be the Ser/ThrPro kinase. TPKI was more effective than TPKII for producing the decrease of tau-1 immunoreactivity and mobility shift of tau on SDS-PAGE. Moreover, TPKI, but not TPKII nor other well-known protein kinases, generated an epitope present on paired helical filaments. These findings suggested that tau phosphorylated by TPKI resembled A-68, a component of paired helical filaments.
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PMID:Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. 158 65

Considerable evidence suggests that altered neuronal calcium homeostasis plays a role in the neuronal degeneration that occurs in an array of neurological disorders. A reduction in microtubules, the accumulation of 8-15 nm straight filaments, and altered antigenicity toward antibodies to the microtubule-associated protein tau and ubiquitin, as well as granulovacuolar degeneration, are observed in many human neurodegenerative disorders. Progress toward understanding how and why human neurons degenerate has been hindered by the inability to examine living human neurons under controlled conditions. We used cultured human fetal cerebral cortical neurons to examine ultrastructural and antigenic changes resulting from elevations in intracellular calcium levels. Elevation of intracellular calcium by exposure to a calcium ionophore or a reduced level of extracellular Na+ for periods of hours to days caused a loss of microtubules, an increase in 8-15 nm straight filaments, and increased immunostaining with Alz-50 and 5E2 (tau antibodies) and ubiquitin antibodies. Granulovacuolar degeneration was also observed. Antigenic changes in tau were sensitive to phosphatases, and the electrophoretic mobility of tau was altered in cells exposed to calcium ionophore, indicating that tau was excessively phosphorylated as the result of elevated intracellular calcium levels. Colchicine also caused an accumulation of straight filaments and altered tau immunoreactivity, suggesting that a disruption of microtubules secondary to altered calcium homeostasis may be a key event leading to altered tau disposition and neuronal degeneration. These data demonstrate that aberrant rises in intraneuronal calcium levels can result in changes in the neuronal cytoskeleton similar to those seen in neurodegenerative disorders, and suggest that this experimental system will be useful in furthering our understanding of the cellular and molecular mechanisms of human neurological disorders.
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PMID:Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons. 166 46

The effects of cAMP-dependent protein kinase (cAMP-PK) phosphorylation on the degradation of the microtubule-associated protein tau by calpain were studied. Purified bovine brain tau that had been phosphorylated by cAMP-PK had a slower migration pattern on sodium dodecyl sulfate-polyacrylamide gels and a more acidic, less heterogeneous pattern on two-dimensional, nonequilibrium pH gradient electrophoresis (NEPHGE) gels compared with untreated tau. Phosphorylation of tau by cAMP-PK significantly inhibited its proteolysis by calpain compared with untreated tau. To our knowledge this is the first demonstration that phosphorylation of tau by a specific kinase results in increased resistance to hydrolysis by calpain. Tau dephosphorylated by alkaline phosphatase migrated more rapidly on sodium dodecyl sulfate-polyacrylamide gels and also showed an altered two-dimensional NEPHGE pattern. Dephosphorylation of tau had no effect on its susceptibility to calpain proteolysis, indicating that regulation of the susceptibility to calpain hydrolysis is due to the phosphorylation of a specific site(s). These results suggest a role for phosphorylation in regulating the degradation of tau. Abnormal phosphorylation could result in a protease-resistant tau population which may contribute to the formation of paired helical filaments in Alzheimer's disease.
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PMID:Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. 173 Jul 2

Abnormal tau proteins (PHF-tau) were isolated from Alzheimer's disease brains by treatment of paired helical filament enriched-fractions with perchloric acid and boiling of the acid precipitable fraction with beta-mercaptoethanol. These proteins were purified further by a second perchloric acid treatment. The purified PHF-tau proteins were soluble in buffers devoid of sodium dodecyl sulfate. However, they were similar to the abnormal tau extracted from paired helical filaments with sodium dodecyl sulfate, also named A68, in molecular mass (68, 64, and 60 kDa), isoelectric point (pI 5.5-6.5), reactivity with anti-tau antibodies, and in requirement for alkaline phosphatase treatment to bind the Tau-1 antibody. Compared to normal tau, the soluble PHF-tau contained 100% more glycine and 35% less lysine residue. The results suggest that besides phosphorylation other types of modification may be involved in differentiating PHF-tau from normal tau.
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PMID:Abnormal tau proteins from Alzheimer's disease brains. Purification and amino acid analysis. 193 96

Microtubule-associated protein tau was purified from bovine brain microtubules by either (1) phosphocellulose chromatography, (2) heat treatment at pH 6.4, (3) heat treatment at pH 2.7, (4) heat treatment at pH 2.7 followed by extraction with perchloric acid and precipitation with glycerol, or (5) by precipitation with ammonium sulfate followed by extraction with perchloric acid. All of these tau preparations reacted specifically with antibodies to Alzheimer paired helical filaments. Affinity purified antibodies to tau labeled both Alzheimer neurofibrillary tangles and plaque neurites but not amyloid in Alzheimer brain tissue sections and labeled paired helical filament polypeptides on Western blots. Human brain tau and paired helical filament polypeptides co-migrated on sodium dodecyl sulfate-polyacrylamide gels. These results suggest that tau is a major component of Alzheimer paired helical filaments.
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PMID:Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. 308 78

Calcium/calmodulin (CaM)-dependent protein kinases isolated from bovine and rat brains phosphorylate the microtubule-associated tau protein in the mode that shifts the mobility of tau in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (mode I). This mode of tau phosphorylation is the one that occurs abnormally in Alzheimer's lesions. Purified tau protein in solution can be phosphorylated by the Ca2+/CaM kinases maximally to about 50% of the total tau protein. Incorporation of one phosphate group per mol of tau is sufficient to shift the protein to a slower migrating electrophoretic band. Additional phosphate incorporation into the shifted tau proteins can occur depending on protein kinase concentration. In the presence of phosphatidylserine, tau proteins were phosphorylated to an extent of 100% at a tau: phosphatidylserine ratio of 20. Phosphatidylethanolamine also stimulated tau phosphorylation by Ca2+/CaM kinase and phosphatidylinositol was found to be a potent inhibitor of tau protein phosphorylation. The direct observation that tau proteins interact with phospholipids such as phosphatidylethanolamine and phosphatidylinositol, resulting in a smearing of the protein band on sodium dodecyl sulfate-gel electrophoresis, supports the possibility that tau protein may interact with phospholipid membranes in vivo and that tau protein phosphorylation could be modulated by the phospholipid composition of the membranes with which tau interacts.
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PMID:Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. 312 1

We have analysed changes in tau protein immunoreactivity in rat embryonic neurons degenerating in response to treatment with N-methyl-D-aspartate (NMDA), non-NMDA and metabotropic agonists. Glutamate agonists were applied in Mg(++)-free and glycine-supplemented medium 8 days after initial plating. Cell viability was assessed by fluorescein diacetate staining and neuronal survival was evaluated by cell counting. Immunocytochemical and confocal laser microscopic studies used a tau2 monoclonal antibody. Acute and chronic NMDA treatment induced a concentration-dependent increase in intraneuronal tau immunoreactivity. Increased tau immunolabelling during chronic NMDA toxicity was dramatically attenuated by tetrodotoxin and also by 6-cyano-7-nitroquinoxaline-2,3-dione. Non-NMDA and metabotropic receptor agonist treatment produced a weaker augmentation in tau2 immunoreactivity. These findings suggest that, in this model, glutamate-receptor and sodium-channel coactivation are together needed to produce changes in tau immunoreactivity.
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PMID:Modulation of tau neuronal expression induced by NMDA, non-NMDA and metabotropic glutamate receptor agonists. 754 Dec 98

In this study, the in situ phosphorylation and subsequent calcium-activated proteolysis of tau protein were examined in human neuroblastoma (LA-N-5) cells, which were differentiated into a neuronal phenotype. The phosphorylation of tau was increased by treating the cells with forskolin and rolipram, which elevate cyclic AMP levels, by treating with the phosphatase inhibitor okadaic acid, or by treating with a combination of both treatments. Phosphorylated tau migrated slightly slower on sodium dodecyl sulfate-polyacrylamide gels than tau from untreated cells. Immunostaining with the phosphate-sensitive monoclonal antibody Tau-1 was also decreased in cells treated with okadaic acid, indicating an increase in the phosphorylation of specific Ser-Pro motifs within the molecule. Calcium-dependent, in situ proteolysis of tau protein was induced by treating the cells with the calcium ionophore A23187. Tau protein was proteolyzed to a significantly lesser extent in cells treated with forskolin and rolipram, okadaic acid, or both than in cells in which phosphorylation was not increased. Partially purified tau protein from cells treated with a combination of forskolin, rolipram, and okadaic acid was also more resistant to proteolysis by calpain in vitro compared with tau isolated from control cells. These data suggest a possible role for phosphorylation in the regulation of tau metabolism and in pathological conditions in which the balance between protein kinases and phosphatases is disrupted.
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PMID:Phosphorylation of tau in situ: inhibition of calcium-dependent proteolysis. 761 52


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